Chediak-Higashi syndrome is a genetic disease of children and mutant strains of mink, mice and cattle. No unifying hypothesis to explain the manifestations of the disorder has previously been formulated and present treatment is essentially symptomatic. We are able to correct all of the defects of CH cells so far studied with carbamylcholine (carbachol) and related agents that elevate 3'5' cyclic GMP (cGMP) levels. Untreated CH cells have several properties in common with colchicine-treated normal cells. Thus our hypothesis is that cGMP generation is defective in the disease and that this defect leads to an abnormality of microtubule (MT) polymerization. Our research effort will be directed towards establishing the mechanism by which related cholinergic drugs reverse the defect in MT dysfunction. In addition, we will explore a new hypothesis that evolved out of our studies with CH cells but is not restricted to these cells. We propose that cGMP levels regulate MT assembly and hence MT-dependent properties of cell surfaces in all cells. Further we propose that defective modulation of cGMP levels in malignant cells is responsible for characteristic abnormalities in several surface properties of cancer cells that are highly correlated with loss of growth control. Experiments to test this hypothesis will provide new insight into the biochemical changes that accompany neoplastic transformation.